The present invention relates to compounds that inhibit certain integrins, particularly to compounds that inhibit xcex1vxcex23 and xcex1IIbxcex23 integrins, their synthesis and their use as integrin inhibitors.
Integrins are a family of cell adhesion receptors. The integrin family of proteins are expressed on the surface of a cell and contain a binding site that binds the cell to certain glycoproteins and therefore mediate cell-cell and cell-extracellular matrix (ECM)interactions.
They are heterodimer transmembrane proteins that consist of an alpha unit and a beta unit. The integrin family has been designated a standard nomenclature system based upon the structure of the alpha unit and the beta unit of the receptor. Therefore, all compounds that have the designation xcex1v each share the same alpha unit. All compounds that have the xcex23 designation have the same beta subunit. The various combinations of those subunits give a wide array of heterodimers with distinct cellular and adhesive specificities.
The family includes cell adhesion receptors such as xcex1IIbxcex23 (previously called GpIIb/IIIa, generally known as the fibrinogen receptor), xcex1vxcex23 (generally known as the vitronectin receptor), and xcex1vxcex25 (generally known as the osteopontin receptor)
Some integrins (including xcex1IIbxcex23, xcex1vxcex23 and xcex1vxcex25) bind to a group of glycoproteins that contain the tripeptide moiety, Arg-Gly-Asp (RGD). While several members of the integrin family members may bind to RGD containing proteins, the physical configuration of the binding site on each protein affects binding affinity between the integrin and the RGD containing glycoprotein. Nonetheless, each integrin may be capable of binding to more than one molecule containing the RGD moiety with differing degrees of effectiveness.
The integrin, xcex1vxcex23, is a particularly important integrin family member that has a wide range of reactivity. It is expressed on a variety of cells, including endothelial cells, osteoclasts, platelets, and smooth muscle cells, and binds to vitronectin and plays an important role in bone resporption, angiogenesis, and neovascularization. The binding of xcex1vxcex23 to vitronectin is an important step in the process of angiogenesis or neovascularization.
Angiogenesis is described as the formation of new blood vessels into a tissue. Angiogenesis is an important process in neonatal growth, but is also important in wound healing and in.the pathogenesis of a large variety of clinically important diseases including tissue inflammation, arthritis, psoriasis, cancer, diabetic retinopathy, macular degeneration and other neovascular eye diseases. These clinical entities associated with angiogenesis are referred to as angiogenic diseases. See Folkman et al., Science, 235:442-447 (1987) and Folkman et al., J. B. C., 267: 10931-10934 (1992).
It has been postulated that the growth of tumors depends on an adequate blood supply, which in turn is dependent on the growth of new vessels into the tumor; thus inhibition of angiogenesis can cause tumor regression in animal models. Integrin antagonists, such as xcex1vxcex23 antagonists which inhibit angiogenesis are therefore useful in the treatment of cancer for inhibiting tumor growth.
Inhibiting angiogenesis will slow or halt the growth of tumors. Inhibition of xcex1vxcex23 is believed to cause tumor regression and induce apoptosis. The xcex1vxcex23 integrin also binds to bone matrix proteins that contain the RGD moiety such as osteopontin, bone sialoprotein and thrombospondin. Inhibition of xcex1vxcex23 is believed to have potential therapeutic value in the prevention of osteoporosis. xcex1vxcex23 is implicated in bone resorption at the level of osteoclasts and in osteoporosis such as described in WO 98/31359, WO 98/08840 and WO 98/18461.
The binding of integrins such as xcex1vxcex23, xcex1vxcex21 and xcex1vxcex25 to fibronectin has been linked to the specific internalization of Neisseria gonorrhoeae bacteria into epithelial cells. Additionally, the binding of RGD containing domain of exogenous HIV-1 Tat protein is believed to decrease the function of dendric cells, possibly impairing antigen presentation.
The integrin, xcex1vxcex25, known primarily as the osteopontin receptor binds to other RGD containing molecules including vitronectin. Inhibitors of xcex1vxcex25 have potential therapeutic value in the treatment in osteoporosis and angiogenesis.
Because of the similarity of molecules in the integrin family, integrins exhibit a considerable degree of cross reactivity as is illustrated above with the discussion regarding the xcex1vxcex23 and xcex1vxcex25 integrins. However, the inhibition of xcex1vxcex23 and xcex1vxcex25 or other integrins are rather unpredictable. One effective inhibitor of xcex1vxcex23 may be also effective inhibitor of xcex1IIbxcex23 but not of xcex1vxcex25. Other inhibitors may selectively inhibit one integrin but not inhibit other integrins. The use of a compound for a particular application may depend upon which integrins it inhibits and to what extent it inhibits other molecules.
There have been several publications which disclose potential inhibitors of xcex1vxcex23. Some of these publications include Haubner et al., xe2x80x9cStructural and Functional Aspects of RGD-Containing Cyclic Pentapeptides as Highly Potent and Selective Integrin xcex1vxcex23 Antagonists,xe2x80x9d J. Am. Chem. Soc., Vol. 118, 7461-7472 (1996); Wong et al., xe2x80x9cStudies on xcex1vb3/Ligand Interactions Using a [3H] SKandF-107260 Binding Assay,xe2x80x9d Molec. Pharm, Vol. 50, pp. 529-537, (1996); Brooks, xe2x80x9cIntegrin xcex1vb3: A Therapeutic Target,xe2x80x9d DNandP Vol. 8(10), pp. 456-460 (1997); Samanen et al., xe2x80x9cVascular Indications for Integrin xcex1v Antagonists,xe2x80x9d Current Pharmaceutical Design, Vol. 3, pp. 545-584 (1997); PCT Pub. No. WO 97/24124 to Smithkline Beecham Corporation ; PCT WO 98/23608 to The Du Pont Merck Pharmaceutical Co; PCT WO 97/36862 to G. D. Searle and Co; PCT WO 97/36859 so G. D. Searle.
There are other publications which disclose inhibitors of other integrins. Some of these publications include PCT Pub. No. WO 94/08577 to Merck and Co.; U.S. Pat. No. 5,084,466 to Alig et al.; PCT Publ. No. WO 97/01540 to Smithkline Beecham Corporation; Kunicki et al., xe2x80x9cExchange of Arg-Gly-Asp (RGD) and Arg-Tyr-Asp (RYD) Binding Sequences in a Recombinant Murine Fab Fragmentxe2x80x9d J. Bio. Chem, Vol. 270, No. 28, pp. 16660-16665 (1995); PCT Publ. No. WO 98/05774 to Merck and Co. Inc; U.S. Pat. No. 5,227,490 to Hartman et al.; U.S. Pat. No. 5,082,942 to Mahuzier; PCT WO 97/26250 to Merck and Co.
However, despite all of the studies on integrin receptor antagonists, there is still a need for compounds that bind to particular integrins effectively and particularly can effectively bind to xcex1v integrins including xcex1vb3 and/or xcex1IIbxcex23. This Invention satisfies these and other needs.
The therapeutic use of certain quinolizinone derivatives has been described previously. For example, Y. Kitaura et al., in U.S. Pat. No. 4,650,804 issued Mar. 17, 1987 have disclosed quinolizinone compounds having a tetrazolylcarbamoyl substitiuent which are useful for the treatment of allergic and ulcer diseases.
J. V. Heck and E. D. Thorsett, in U.S. Pat. No 4,921,857 issued May 1, 1990 have disclosed the use of certain 4-oxo-4H-quinolizine-3-carboxylic acids and derivatives thereof for treating bacterial infections.
Y. Kurashiva et Al. in U.S. Pat. No. 4,935,425 issued Jun. 19, 1990 have disclosed 4H-quinolizin-4-ones for treatment of diseases associated with immunoglobulin E-antibody formation. However, quinolizinone compounds have not been described for the use of angiogenesis inhibitors.
Presently, there is a need to identify compounds which bind to integrin receptors. There is a further need to identify compounds which bind to the (xcex1vxcex23 receptor as well as the xcex1IIbxcex23 receptor both individually and collectively.
Additionally, there is a present need to identify integrin antagonist compounds which are useful agents for inhibiting and arresting angiogenesis. The present invention satisfies these and other needs.
The present invention comprises novel compounds that are effective inhibitors of integrins, particularly xcex1IIbxcex23 or xcex1v integrins such as xcex1vxcex23 and xcex1vxcex25.
The present invention, according to one embodiment, comprises a compound of formula (I) or formula (II): 
or a pharmaceutically acceptable salt, solvate, or metabolic precursor thereof.
According this embodiment of the present invention, one of R1 and R2 is xe2x80x94Jxe2x80x94Kxe2x80x94L, and the other is H. Furthermore, one of R3 and R4 is xe2x80x94Xxe2x80x94Yxe2x80x94Z, and the other is H.
According to this embodiment of the present invention, J is selected from the group consisting of:
xe2x80x94(CH2)mxe2x80x94, xe2x80x94(CH2)mCR5xe2x95x90CR7(CH2)nxe2x80x94, xe2x80x94(CH2)mCxe2x89xa1C(CH2)nxe2x80x94, xe2x80x94(CH2)mO(CH2)nxe2x80x94, xe2x80x94(CH2)mS(CH2)nxe2x80x94, xe2x80x94(CH2)mNR5(CH2)nxe2x80x94, xe2x80x94(CH2)mCO(CH2)nxe2x80x94, xe2x80x94(CH2)mCS(CH2)nxe2x80x94, xe2x80x94(CH2)mSO2(CH2)nxe2x80x94, xe2x80x94(CH2)mSO(CH2)nxe2x80x94, xe2x80x94(CH2)mC(O)O(CH2)nxe2x80x94, xe2x80x94(CH2)mOC(O)(CH2)nxe2x80x94, xe2x80x94(CH2)mSO2NR5(CH2)nxe2x80x94, xe2x80x94(CH2)mNR5SO2(CH2)nxe2x80x94, xe2x80x94(CH2)mCONR5(CH2)nxe2x80x94, xe2x80x94(CH2)mNR5CO(CH2)nxe2x80x94, xe2x80x94(CH2)mNR5(CH2)nCONHxe2x80x94, xe2x80x94(CH2)mO(CH2)nCONHxe2x80x94, xe2x80x94(CH2)mNH(CH2)nSCSNR5xe2x80x94, xe2x80x94(CH2)mNH(CH2)nSCNHNH2xe2x80x94, a heterocycle optionally linked by an amine, where m and n are independently integers from 0-6. R5 and R7 of J are independently selected from the group consisting of hydrogen, C1-10alkyl, C1-10alkenyl, C1-10alkynyl, C0-8alkylaryl, and C3-10cycloalkyl.
According to this embodiment, K is selected from the group consisting of:
xe2x80x94C1-8alkyl-, xe2x80x94C3-15cycloalkyl-, xe2x80x94C6-15aryl-, xe2x80x94C6-15aryl-C1-8alkyl-, xe2x80x94C1-8alkyl-C6-15aryl-, xe2x80x94C1-8alkenyl-, xe2x80x94C1-8alkynyl-, xe2x80x94(CH2)qNR6xe2x80x94, xe2x80x94CONR6xe2x80x94, xe2x80x94NHC(O)OCH2xe2x80x94C6-8aryl-, xe2x80x94CNHNH2xe2x80x94, a heterocycle and an amine linked heterocycle; L is selected from the group consisting of xe2x80x94H, xe2x80x94C1-10alkyl, xe2x80x94C3-10cycloalkyl, a 5-10 member heterocycle, xe2x80x94C6-10aryl, xe2x80x94C1-10alkyl-C6-10aryl, xe2x80x94NHR12, xe2x80x94NR13C(N)NHR12, xe2x80x94C(N)NHR12, xe2x80x94C(O)NHR12, xe2x80x94NR13C(O)NHR12, xe2x80x94SC(N)NHR12, xe2x80x94SC(S)NHR12, xe2x80x94OC(N)NHR12, xe2x80x94OC(O)NHR12 and xe2x80x94C(O)OR12.
In the definition of K, q is an integer of between 0 and 6.
R6 and R13 of K are independently selected from the group consisting of hydrogen, C1-10alkyl, C1-10alkenyl, C1-10alkynyl, C0-8alkylaryl, and C3-10cycloalkyl. R12 is independently selected from the group consisting of xe2x80x94C1-10alkyl, xe2x80x94C3-10cycloalkyl, a xe2x80x94C0-8alkyl-C6-10aryl, or a 5-10 member heterocycle optionally linked by a C1-10alkyl or an amine.
According to this embodiment, X is selected from the group consisting of:
xe2x80x94(CH2)oxe2x80x94, xe2x80x94(CH2)oCR5xe2x95x90CR7(CH2)pxe2x80x94, xe2x80x94(CH2)oCxe2x89xa1C(CH2)pxe2x80x94, xe2x80x94(CH2)oO(CH2)pxe2x80x94, xe2x80x94(CH2)oS(CH2)pxe2x80x94, xe2x80x94(CH2)oNR5(CH2)pxe2x80x94, xe2x80x94(CH2)oCO(CH2)pxe2x80x94, xe2x80x94(CH2)oCS(CH2)pxe2x80x94, xe2x80x94(CH2)oSO2(CH2)pxe2x80x94, xe2x80x94(CH2)oSO(CH2)pxe2x80x94, xe2x80x94(CH2)oC(O)O(CH2)pxe2x80x94, xe2x80x94(CH2)oOC(O)(CH2)pxe2x80x94, xe2x80x94(CH2)oSO2NR5(CH2)pxe2x80x94, xe2x80x94(CH2)oNR5SO2(CH2)pxe2x80x94, xe2x80x94(CH2)oCONR5(CH2)pxe2x80x94, xe2x80x94(CH2)oNR5CO(CH2)pxe2x80x94, xe2x80x94(CH2)oNR5CONR7(CH2)pxe2x80x94, xe2x80x94(CH2)oNR5(CH2)pCONHxe2x80x94, xe2x80x94(CH2)oO(CH2)pCONHxe2x80x94, xe2x80x94(CH2)oNH (CH2)pSCSNR5xe2x80x94, and xe2x80x94(CH2)oNH(CH2)pSCNHNHxe2x80x94, where o and p are independently integers from 0-6.
Additionally, R5 and R7 of X are independently selected from the group consisting of hydrogen, C1-10alkyl, C1-10alkenyl, C1-10alkynyl, C0-8alkylaryl, and C3-10cycloalkyl.
According to this embodiment, Y is selected from the group consisting of:
xe2x80x94(CH2)qxe2x80x94, C6-8aryl-, a C3-10cycloalkyl or 
where q and r of Y are independently integers of 0-4 and the sum of s and t is an integer of between 4 and 8.
As defined above, R8, R9, R10, and R11 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, xe2x80x94NR5SO2C6-10aryl, C6-10aryl-C1-6alkyl-C6-10aryl, a 5-10 member heterocycle, an amine linked 5-10 member heterocycle, and a 5-10 member heterocycle linked by a C1-6alkyl.
Z, of this embodiment, is selected from the group consisting of xe2x80x94H, xe2x80x94COOH, xe2x80x94C(O)OR14 and xe2x80x94SO2R14, R14 is selected from the group consisting of xe2x80x94C1-10alkyl, xe2x80x94C3-10cycloalkyl, a xe2x80x94C0-8alkyl-C6-10aryl, or a 5-10 member heterocycle optionally linked by a C1-10alkyl or an amine.
Other embodiments of the present invention include specific compounds and general formula disclosed in the detailed description below.
Another aspect of the invention is a process for preparing a compound of formula I or II. The method comprises preparing a
Compound according to Scheme A herein. Other embodiments of the invention include preparation of compounds according to any of the schemes or processes disclosed in the detailed description below.
Another aspect of the present invention includes a method for treatment of cancer comprising administering a pharmaceutically effective amount of the compound of formula I or II as defined herein to a patient, Other embodiments of the invention include methods of treatment as set forth in the detailed description.
Yet another aspect of the present invention includes a method for treatment of tumors comprising administering a pharmaceutically effective amount of the compound of formula I or II as defined herein to a patient.
Yet another aspect of the present invention includes a method for inhibiting an xcex1vxcex23, xcex1vxcex25 or xcex1IIbxcex23 integrin in vivo comprising administering a pharmaceutically effective amount of the compound of formula I or II to a patient.
List of Schemes:
Scheme A: Preparation of a 7,3 Quinolizinone Framework
Scheme B: Preparation of a 7,2 and 8,2 xe2x80x94Quinolizinone Framework
Scheme C: Preparation of a 7,2 and 8,2 Substituted Quinolizinone Integrin Inhibitors
Scheme D: Preparation of a 7 or 8 Aminomethyl Linked Quinolizinone Framework
Scheme E: Preparation of a 7 or 8 Aminomethyl Linked Tetrahydroquinolizinone Framework
Scheme F: Preparation of a 8,3 and 8,2 Substituted Quinolizinone Series Bearing an Amino Linker in the xe2x80x94Lxe2x80x94Kxe2x80x94J Group.
Scheme G: Solid Phase Approach Used to Synthesize the 8,3 Series Quinolizinones
The present invention comprises novel compounds that are effective inhibitors of integrins including xcex1v and/or xcex1IIbxcex23 integrins as well as an effective medicament for the inhibition of angiogenesis and thereby treatment of tumors and cancer.
One embodiment of the present invention comprises a compound of formula (I) or formula (II): 
or a pharmaceutically acceptable salt, solvate, or metabolic precursor thereof.
According to this embodiment, one of R1 and R2 is xe2x80x94Jxe2x80x94Kxe2x80x94L, and the other is H. Furthermore, one of R3 and R4 is xe2x80x94Xxe2x80x94Yxe2x80x94Z, and the other is H.
According to this embodiment, J is selected from the group consisting of:
xe2x80x94(CH2)mxe2x80x94, xe2x80x94(CH2)mCR5xe2x95x90CR7(CH2)nxe2x80x94, xe2x80x94(CH2)mCxe2x89xa1C(CH2)nxe2x80x94, xe2x80x94(CH2)mO(CH2)nxe2x80x94, xe2x80x94(CH2)mS(CH2)nxe2x80x94, xe2x80x94(CH2)mNR5(CH2)nxe2x80x94, xe2x80x94(CH2)mCO(CH2)nxe2x80x94, xe2x80x94(CH2)mCS(CH2)nxe2x80x94, xe2x80x94(CH2)mSO2(CH2)nxe2x80x94, xe2x80x94(CH2)mSO(CH2)nxe2x80x94, xe2x80x94(CH2)mC(O)O(CH2)nxe2x80x94, xe2x80x94(CH2)mOC(O)(CH2)nxe2x80x94, xe2x80x94(CH2)mSO2NR5(CH2)nxe2x80x94, xe2x80x94(CH2)mNR5SO2(CH2)nxe2x80x94, xe2x80x94(CH2)mCONR5(CH2)nxe2x80x94, xe2x80x94(CH2)mNR5CO(CH2)nxe2x80x94, xe2x80x94(CH2)mNR5(CH2)nCONHxe2x80x94, xe2x80x94(CH2)mO(CH2)nCONHxe2x80x94, xe2x80x94(CH2)mNH(CH2)nSCSNR5xe2x80x94, xe2x80x94(CH2)mNH(CH2)nSCNHNH2xe2x80x94, and a heterocycle optionally linked by an amine, where m and n are independently integers from 0-6. R5 and R7 of J are independently selected from the group consisting of hydrogen, C1-10alkyl, C1-10alkenyl, C1-10alkynyl, C1-8alkylaryl, and C3-10cycloalkyl.
According to this embodiment, K is selected from the group consisting of:
xe2x80x94C1-8alkyl-, xe2x80x94C3-15cycloalkyl-, xe2x80x94C6-15aryl-, xe2x80x94C6-15aryl-C1-8alkyl-, xe2x80x94C1-8alkyl-C6-15aryl-, xe2x80x94C1-8alkenyl-, xe2x80x94C1-8alkynyl-, xe2x80x94(CH2)qNR6xe2x80x94, xe2x80x94CONR6xe2x80x94, xe2x80x94NHC(O)OCH2xe2x80x94C6-8 aryl-, xe2x80x94CNHNH2xe2x80x94, a heterocycle and an amine linked heterocycle, where q of K is an integer between 0 and 6.
Additionally, L is selected from the group consisting of
xe2x80x94H, xe2x80x94C1-10alkyl, xe2x80x94C3-10cycloalkyl, a 5-10 member heterocycle, xe2x80x94C6-10aryl, xe2x80x94C1-10 alkyl-C6-10aryl, xe2x80x94NHR12, xe2x80x94NR13C(N)NHR12, xe2x80x94C(N)NHR12, xe2x80x94C(O)NHR12, xe2x80x94NR13C(O)NHR12, xe2x80x94SC(N)NHR12, xe2x80x94SC(S)NHR12, xe2x80x94OC(N)NHR12, xe2x80x94OC(O)NHR12, and xe2x80x94C(O)OR12.
R6 and R13 of K are independently selected from the group consisting of hydrogen, C1-10alkyl, C1-10alkenyl, C1-10alkynyl, C0-8alkylaryl, and C3-10cycloalkyl. R12 is independently selected from the group consisting of xe2x80x94C1-10alkyl, xe2x80x94C3-10cycloalkyl, a xe2x80x94C0-8alkyl-C6-10aryl, and a 5-10 member heterocycle optionally linked by a C1-10alkyl or an amine.
According to this embodiment, X is selected from the group consisting of:
xe2x80x94(CH2)oxe2x80x94, xe2x80x94(CH2)oCR5xe2x95x90CR7(CH2)pxe2x80x94, xe2x80x94(CH2)oCxe2x89xa1C(CH2)pxe2x80x94, xe2x80x94(CH2)oO(CH2)pxe2x80x94, xe2x80x94(CH2)oS(CH2)pxe2x80x94, xe2x80x94(CH2)oNR5(CH2)pxe2x80x94, xe2x80x94(CH2)oCO(CH2)pxe2x80x94, xe2x80x94(CH2)oCS(CH2)pxe2x80x94, xe2x80x94(CH2)oSO2(CH2)pxe2x80x94, xe2x80x94(CH2)oSO(CH2)pxe2x80x94, xe2x80x94(CH2)oC(O)O(CH2)pxe2x80x94, xe2x80x94(CH2)oOC(O)(CH2)pxe2x80x94, xe2x80x94(CH2)oSO2NR5(CH2)pxe2x80x94, xe2x80x94(CH2)oNR5SO2(CH2)pxe2x80x94, xe2x80x94(CH2)oCONR5(CH2)pxe2x80x94, xe2x80x94(CH2)oNR5CO(CH2)pxe2x80x94, xe2x80x94(CH2)oNR5CONR7(CH2)pxe2x80x94, xe2x80x94(CH2)oNR5(CH2)pCONHxe2x80x94, xe2x80x94(CH2)oO(CH2)pCONHxe2x80x94, xe2x80x94(CH2)oNH(CH2)pSCSNR5xe2x80x94, and xe2x80x94(CH2)oNH(CH2)pSCNHNH2xe2x80x94, where o and p are independently integers from 0-6. Additionally, R5 and R7 of X are independently selected from the group consisting of hydrogen, C1-10alkyl, C1-10alkenyl, C1-10alkynyl, C0-8alkylaryl, and C3-10cycloalkyl.
According to this embodiment, Y is selected from the group consisting of:
xe2x80x94(CH2)qxe2x80x94, C6-8aryl-, a C3-10cycloalkyl and 
where q and r of Y are independently integers of 0-4 and the sum of s and t is an integer of between 3 and 8.
As defined above, R8, R9, R10 and R11 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, xe2x80x94NR5SO2C6-10aryl, C6-10aryl, C1-6alkyl-C6-10aryl, a 5-10 member heterocycle, an amine linked 5-10 member heterocycle, and a 5-10 member heterocycle linked by a C1-6alkyl.
Z, of this embodiment, is selected from the group consisting of xe2x80x94H, xe2x80x94COOH, xe2x80x94C(O)OR14 and xe2x80x94SO2R14. R14 is selected from the group consisting of xe2x80x94C1-10alkyl, xe2x80x94C3-10cycloalkyl, a xe2x80x94C0-8alkyl-C6-10aryl, or a 5-10 member heterocycle optionally linked by a C1-10alkyl and an amine.
In another embodiment, the present invention comprises a compound of formula I otherwise as previously defined.
Another embodiment, of the present invention comprises the compound of formula II otherwise as previously defined.
In another embodiment, the present invention comprises a compound of formula I or formula II as previously defined except that R1 and R3 are both H and R2 is xe2x80x94Jxe2x80x94Kxe2x80x94L and R4 is xe2x80x94Xxe2x80x94Yxe2x80x94Z.
In another embodiment, the present invention comprises a compound of formula I or formula II as previously defined except that R1 and R4 are both H and R2 is xe2x80x94Jxe2x80x94Kxe2x80x94L and R3 is xe2x80x94Xxe2x80x94Yxe2x80x94Z.
In another embodiment, the present invention comprises a compound of formula I or formula II as previously defined except that R2 and R3 are both H and R1 is xe2x80x94Jxe2x80x94Kxe2x80x94L and R4 is xe2x80x94Xxe2x80x94Yxe2x80x94Z.
In another embodiment, the present invention comprises a compound of formula I or formula II as previously defined except that R2 and R4 are both H and R2 is xe2x80x94Jxe2x80x94Kxe2x80x94L and R3 is xe2x80x94Xxe2x80x94Yxe2x80x94Z.
In another embodiment, the present invention comprises a compound of formula I or formula II as previously defined except that J is selected from the group consisting of:
xe2x80x94(CH2)mxe2x80x94, xe2x80x94(CH2)mCR5xe2x95x90CR7(CH2)nxe2x80x94, xe2x80x94(CH2)mCxe2x89xa1C(CH2)nxe2x80x94, xe2x80x94(CH2)mO(CH2)nxe2x80x94, xe2x80x94(CH2)mS(CH2)nxe2x80x94, xe2x80x94(CH2)mNR5(CH2)nxe2x80x94, xe2x80x94(CH2)mCO(CH2)nxe2x80x94, xe2x80x94(CH2)mCS(CH2)nxe2x80x94, xe2x80x94(CH2)mSO2(CH2)nxe2x80x94, xe2x80x94(CH2)mSO(CH2)nxe2x80x94, xe2x80x94(CH2)mC(O)O(CH2)nxe2x80x94, xe2x80x94(CH2)mOC(O)(CH2)nxe2x80x94, xe2x80x94(CH2)mSO2NR5(CH2)nxe2x80x94, xe2x80x94(CH2)mNR5SO2(CH2)nxe2x80x94, xe2x80x94(CH2)mCONR5(CH2)nxe2x80x94, xe2x80x94(CH2)mNR5CO(CH2)nxe2x80x94, and an amine linked 5-10 member heterocycle, where m and n are independently integers from 0-6.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that J is selected from the group consisting of
xe2x80x94(CH2)mxe2x80x94, xe2x80x94(CH2)mCxe2x89xa1C(CH2)nxe2x80x94, xe2x80x94(CH2)mCR5xe2x95x90CR7(CH2)nxe2x80x94, xe2x80x94(CH2)mO(CH2)nxe2x80x94, xe2x80x94(CH2)mS(CH2)nxe2x80x94, xe2x80x94(CH2)mNR5(CH2)nxe2x80x94, and an amine linked 5-10 member heterocycle; and wherein m and n are independently integers from 0-3.
According to this embodiment, m is preferably an integer between 0-1 and more preferably m is 0. According to this embodiment, n is preferably an integer between 0-1, and most preferably n is 0.
Also according to one aspect of this embodiment, R5 and R7 are preferably xe2x80x94H or xe2x80x94CH3 and most preferably R5 and R7 are xe2x80x94H.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that K is selected from the group consisting of:
xe2x80x94C1-8alkyl-, xe2x80x94C3-15cycloalkyl-, xe2x80x94C6-15aryl-, xe2x80x94C6-15aryl-C1-8alkyl-, xe2x80x94C1-8alkyl-C6-15aryl-, xe2x80x94C1-8alkenylxe2x80x94, xe2x80x94C1-8alkynyl-, a 5-15 member heterocycle, and an amine linked 5-15 member heterocycle.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that K is a xe2x80x94C1-8alkyl- or a xe2x80x94C3-15 cycloalkyl-.
In another embodiment, K is preferably a xe2x80x94C1-3alkyl- and most preferably a xe2x80x94C1alkyl-.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that K is preferably a xe2x80x94C5-8cycloalkyl-.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that L is selected from the group consisting of a 5-10 member heterocycle, xe2x80x94NHR12, xe2x80x94NR13C(N)NHR12, xe2x80x94C(N)NHR12, xe2x80x94C(O)NHR12, xe2x80x94NR13C(O)NHR12, xe2x80x94SC(N)NHR12, xe2x80x94SC(S)NHR12, xe2x80x94OC(N)NHR12, xe2x80x94OC(O)NHR12, and xe2x80x94C(O)OR12.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that L is selected from the group consisting of:
a 5-10 member heterocycle, C6-10aryl, xe2x80x94NH2R12, xe2x80x94NR13C(N)NHR12, xe2x80x94C(N)NHR12, xe2x80x94C(O)NHR12, xe2x80x94NR13C(O)NHR12, xe2x80x94SC(N)NHR12, xe2x80x94SC(S)NHR12, and xe2x80x94OC(N)NHR12.
According to one aspect of this embodiment, R13 is preferably a C1-5alkyl or H; and most preferably R13 is H.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that R12 is selected from the group consisting of xe2x80x94C1-10alkyl, xe2x80x94C3-10cycloalkyl, or a xe2x80x94C0-8alkyl-C6-10aryl, and a 5-10 member heterocycle optionally linked by a C1-10alkyl.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that R12 is a 5-6 member aromatic heterocycle containing between one and three heteroatoms optionally linked by a C1-2alkyl or an amine.
In another embodiment, R12 is a C6aryl optionally linked by a C1-2alkyl or an amine.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that R12 is a heterocycle optionally linked by a C1-2alkyl or an amine, wherein said heterocycle is selected from the group consisting of pyridine, pyrimidine, piperazine, pyrrole, furan, imidazole, oxazole, pyrazole, pyrroline, and pyrrolidine.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that X is selected from the group consisting of:
xe2x80x94(CH2)oSO2(CH2)pxe2x80x94, xe2x80x94(CH2)oC(O)O(CH2)pxe2x80x94, xe2x80x94(CH2)oOC(O)(CH2)pxe2x80x94, xe2x80x94(CH2)oSO2NR5(CH2)pxe2x80x94, xe2x80x94(CH2)oNR5SO2(CH2)pxe2x80x94, xe2x80x94(CH2)oCONR5(CH2)pxe2x80x94, xe2x80x94(CH2)oNR5CO(CH2)pxe2x80x94, xe2x80x94(CH2)oNR5CONR7(CH2)pxe2x80x94, where o and p are independently integers from 0-6.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that X is selected from the group consisting of xe2x80x94(CH2)oCONHxe2x80x94, and xe2x80x94(CH2)oNR5CONR7(CH2)pxe2x80x94.
In another embodiment, o is preferably an integer from 0-2; p is and integer from 0-2. Most preferably, according to one embodiment, o and p are 0.
According to one embodiment R5 and R7 are independently H or a C1-4alkyl. Most preferably, according to this embodiment, R5 and R7 are both H.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that Y is selected from the group consisting of: 
According to one embodiment, q is an integer of 0-2; most preferably, q is 0.
According to one embodiment, r is an integer of 0-2; and most preferably r is 0.
According to one embodiment, the sum of s and t is an integer of between 3 and 5, and is most preferably 4.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that Y is 
wherein q and r are independently integers of 0-1;
wherein R8 , R9, R10, and R11 are independently selected from the group consisting of H, xe2x80x94NR5SO2C6-10aryl, C6-10aryl, C1-6alkyl-C6-10aryl, NR5C6-10aryl, a 5-10 member heterocycle, a 5-10 member heterocycle linked by a C1-6alkyl and an amine linked 5-10 member heterocycle.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that one of R8 and R9 is not H and the other is H, and R10 and R11 are both H.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that one of R8 and R9 is selected from the group consisting of:
xe2x80x94NR5SO2C6aryl, C6aryl, C1-2alkyl-C6aryl, a 6 member heterocycle, a 6 member heterocycle linked by a C1-2alkyl, and an amine linked 6 member heterocycle.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that one of R8 and R9 is either a six member heterocycle containing 0-3 nitrogen atoms or a phenyl substituted alternatively with one to three substituents selected from the group consisting of C1-4alkyl, flourine, chlorine, bromine, and iodine.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that one of said R8 and R9 is a heterocycle optionally linked by a C1-2alkyl or an amine, wherein said heterocycle is selected from the group consisting of pyridine, pyrimidine, piperazine, pyrrole, furan, imidazole, oxazole, pyrazole, piperidine, morpholine, thiomorpholine, thiophene, pyrroline, and pyrrolidine.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that Z is selected from the group consisting of xe2x80x94H, xe2x80x94COOH, and xe2x80x94C(O)OR14.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that Z is selected from the group consisting of xe2x80x94H and xe2x80x94COOH.
In yet another embodiment, the invention is a pharmaceutical composition comprising a compound of formula I and II as previously defined and a pharmaceutically acceptable excipient.
Another embodiment of the present invention includes a compound of formula I or formula II as defined as follows: J, of this embodiment is selected from the group consisting of: xe2x80x94(CH2)mxe2x80x94, xe2x80x94(CH2)mO(CH2)nxe2x80x94, and xe2x80x94(CH2)mNR5(CH2)n; m and n are independently integers between 0 and 6. R5 and R7 for J are independently selected from the group consisting of hydrogen and C1-4 alkyl.
K of this embodiment is selected from the group consisting of:
xe2x80x94C1-8alkyl-, a xe2x80x94C3-15 cycloalkyl-, and a 5-10 member heterocycle.
L of this embodiment is selected from the group consisting of:
a 5-10 member heterocycle, C6-10aryl, xe2x80x94NH2R12, xe2x80x94NR13C(N)NHR12, xe2x80x94C(N)NHR12, xe2x80x94C(O)NHR12, xe2x80x94NR13C(O)NHR12, xe2x80x94SC(N)NHR12, xe2x80x94SC(S)NHR12, and xe2x80x94OC(N)NHR12; R13 of L is selected from the group consisting of hydrogen and C1-4 alkyl. R12 of L is selected from the group consisting of a xe2x80x94C1-4alkyl, a xe2x80x94C0-4alkyl-C6-7aryl and a 5-10 member heterocycle optionally linked by a C1-10alkyl or an amine.
X of this embodiment is selected from the group consisting of:
xe2x80x94(CH2)oCONHxe2x80x94, xe2x80x94(CH2)oNR5CONR7(CH2)pxe2x80x94; o and p are independently integers from 0 to 6. R5 and R7 of X are independently selected from the group consisting of hydrogen and C1-4 alkyl.
Y of this embodiment is selected from the group consisting of: xe2x80x94(CH2)qxe2x80x94, 
Accordingly, q, r, s, and t of Y are independently integers of 0-4. The sum of s and t is an integer between 3 and 8. R8, R9, R10, and R11 are independently selected from the group consisting of H. xe2x80x94NR5SO2C6-10aryl, C6-10aryl, C1-6alkyl-C6-10aryl, xe2x80x94NR5C6-10aryl, a 5-10 member heterocycle, a 5-10 member heterocycle linked by a C1-6alkyl and an amine linked 5-10 member heterocycle.
Z of this embodiment is selected from the group consisting of xe2x80x94H and xe2x80x94COOH.
According to one embodiment of the present invention, the compound is of formula I and is otherwise as previously defined.
According to one embodiment of the present invention, the compound is of formula II and is otherwise as previously defined.
According to an aspect of this embodiment, m is an integer between 0-1.
According to an aspect of this embodiment, n is an integer between 0-1.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that R5 and R7 of J are independently xe2x80x94H or a C1-4alkyl; most preferably, xe2x80x94H.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that K is a xe2x80x94C1alkyl-.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that K is a C5-8cycloalkyl-.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that R13 of L is a C1-5alkyl or H.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that R12 of L is a 5-6 member aromatic heterocycle containing between one and three heteroatoms optionally linked by a C1-2alkyl or an amine.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that R12 of L is a C6aryl optionally linked by a C1-2alkyl or an amine.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that o of X is an integer from 0-1.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that p of X is an integer from 0-1.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that R5 and R7 of X are independently H or a C1-4alkyl.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that q and r of Y are independently integers of 0-1.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that the sum of s and t is 4.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that Y is 
wherein q and r are independently integers of 0-1;
wherein R8, R9, R10, and R11 are independently selected from the group consisting of H, xe2x80x94NR5SO2C6-10aryl, C6-10aryl, C1-6alkyl-C6-10aryl, NR5C5-10aryl, a 5-10 member heterocycle, a 5-10 member heterocycle linked by a C1-6alkyl and an amine linked 5-10 member heterocycle.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that R8 and R9 is not H and the other is H, and R10 and R11 are both H.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that R8 and R9 is selected from the group consisting of:
xe2x80x94NR5SO2C6aryl, C6aryl, C1-2alkyl-C6aryl, a 6 member heterocycle, a 6 member heterocycle linked by a C1-2alkyl, and an amine linked 6 member heterocycle.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that R8 and R9 is either a six member heterocycle containing 0-3 nitrogen atoms or a phenyl substituted alternatively with one to three substituents selected from the group consisting of C1-4alkyl, flourine, chlorine, bromine, and iodine.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that R8 and R9 is a heterocycle optionally linked by a C1-2alkyl or an amine, wherein said heterocycle is selected from the group consisting of pyridine, pyrimidine, piperazine, pyrrole, furan, imidazole, oxazole, pyrazole, pyrroline, piperidine, morpholine, thiomorpholine, and thiophene and pyrrolidine.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that R3 is H and R4 is JKL. According to this embodiment, J is selected from the group consisting of xe2x80x94(CH2)mxe2x80x94 and xe2x80x94(CH2)mO(CH2)nxe2x80x94, wherein m and n are independently integers from 0-3. K is a xe2x80x94C1-8alkyl-. L is selected from the group consisting of xe2x80x94NH2 and 
According to this embodiment, X is xe2x80x94(CH2)oCONHxe2x80x94, o is an integer from 0-3.
In another embodiment, Y is selected from the group consisting of: 
wherein q, r, s, and t are independently integers of 0-4, and the sum of s and t is 4. Z is xe2x80x94COOH. R15, R16, and R17 are independently selected from the group consisting of xe2x80x94H, C1-4alkyl and halogen (F, Cl, Br, and I).
In another embodiment, the present invention comprises formula I or formula II as previously defined except that R3 is H and R4 is JKL. According to this embodiment, J is selected from the group consisting of:
xe2x80x94(CH2)mO(CH)nxe2x80x94, where m and n are independently integers from 0-3.
According to this embodiment, K is selected from the group consisting of xe2x80x94C1-8alkyl-. L is selected from the group consisting of xe2x80x94NH2, 
According to this embodiment, X is selected from the group consisting of: xe2x80x94(CH2)oCONHxe2x80x94 and xe2x80x94(CH2)oNR5CONR7(CH2)pxe2x80x94, where o and p are independently integers from 0-3.
Also according to this embodiment, Y is selected from the group consisting of: 
where q, r, s, and t are independently integers of 0-4, and wherein the sum of s and t is 4. Additionally, R15, R16, and R17 are independently selected from the group comprising C1-4alkyl, H, and halogen (F, Cl, Br, I).
Also according to this embodiment, R5, R6, and R7 are, for each structure they represent, independently selected from the group consisting of: hydrogen and C1-4 alkyl.
According to this embodiment, Z is xe2x80x94COOH.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that R1 is XYZ and R2 is H. According to this embodiment, R3 is JKL and R4 is H. J is xe2x80x94(CH2)mO(CH2)nxe2x80x94, where m and n are independently integers from 0-3.
K is xe2x80x94C1-8alkyl-; L is selected from the group consisting of
xe2x80x94NH3 and 
According to this embodiment, X is xe2x80x94(CH2)oCONHxe2x80x94, where o is an integer from 0-3. Y is selected from the group consisting of: 
R15, and R16, R17 are independently selected from the group comprising C1-4alkyl, H, and halogen (F, Cl, Br, I).
According to this embodiment, Z is xe2x80x94COOH.
In another embodiment, the present invention comprises formula I or formula II as previously defined except that R1 is XYZ, R2 is H, R3 is H, and R4 is JKL. According to this embodiment, j is selected from the group consisting of:
xe2x80x94Nxe2x80x94, xe2x80x94N(CH3)xe2x80x94, and an amine linked heterocycle.
K is selected from the group consisting of:
xe2x80x94C1-8alkyl- and xe2x80x94C3-15cycloalkyl-.
L is selected from the group consisting of
xe2x80x94NH2, 
According to this embodiment, X is xe2x80x94(CH2)oCONHxe2x80x94, where o is an integer from 0-3. Y is selected from the group consisting of: 
wherein R15, R16, and R17 are independently selected from the group consisting of C1-4alkyl, H, and halogen (F, Cl, Br, I).
According to this embodiment, Z is xe2x80x94COOH.
In another embodiment, the present invention comprises formula I or Formula II as previously defined except that L is selected from the group consisting of xe2x80x94NH2, 
In another embodiment, the present invention comprises formula I or formula II as previously defined except that Y is selected from the group consisting of 
wherein q, r, s, and t are independently integers of 0-4 and the sum of s and t is an integer between 3 and 8. Additionally, R15, R16, and R17 are independently selected from the group consisting of xe2x80x94H, C1-4alkyl and halogen (F, Cl, Br, and I)
Particularly, according to one embodiment the present invention is a compound is of the following formula I or II: 
wherein one of R1 and R2 is xe2x80x94Jxe2x80x94Kxe2x80x94L, and the other is H; and one of R3 and R4 is xe2x80x94Xxe2x80x94Yxe2x80x94Z, and the other is H;
wherein J and X are independently selected from the group consisting of:
xe2x80x94(CH2)mxe2x80x94; xe2x80x94(CH2)mO(CH2)nxe2x80x94; xe2x80x94(CH2)mNR5(CH2)nxe2x80x94; xe2x80x94(CH2)mSO2(CH2)nxe2x80x94; xe2x80x94(CH2)mS(CH2)nxe2x80x94; xe2x80x94(CH2)mSO(CH2)nxe2x80x94; xe2x80x94(CH2)mCO2R5xe2x80x94; xe2x80x94(CH2)mSO2NR5(CH2)nxe2x80x94; xe2x80x94(CH2)mNR5SO2(CH2)nxe2x80x94; xe2x80x94(CH2)mCR5xe2x95x90CR7(CH2)nxe2x80x94; xe2x80x94(CH2)mCONHxe2x80x94; xe2x80x94(CH2)mNR5(CH2)nCONHxe2x80x94; xe2x80x94(CH2)mO(CH2)nCONHxe2x80x94; xe2x80x94(CH2)mN(CH2)nSCSNHR5xe2x80x94; xe2x80x94(CH2)mN(CH2)nSCNHNH2xe2x80x94; and a heterocyclic ring, which is unsubstituted or substituted with xe2x80x94CNR5NH2; 
wherein m and n are independently integers from 0-6;
or xe2x80x94Xxe2x80x94Yxe2x80x94Z together are Cl or COOH;
wherein K is selected from the group consisting of: hydrogen, C1-8alkyl, C6-15aryl C1-8 alkyl, C1-8 alkenyl; C1-8 alkynyl; C3-15 cycloalkyl; NH2; NHHeterocycle; HCONHR6; NCO2CH2C6-8aryl; NR5CNHNH2; and Heterocycle(CH2)mCOOR5; wherein Y is selected from the group consisting of: hydrogen, CR8R9CR10R11COOR5; C6-8aryl; C3-10 cycloalkyl which is unsubstituted or substituted with COOH or NR5CNHNH2; Heterocycle(CH2)mCOOR5; (CH)qCH(CH)r; 
wherein q, r, s, and t are independently integers of 0-4;
L and Z are independently selected from the group consisting of H, C1-10 alkyl, and C3-10 cycloalkyl; wherein R5, R6 and R7 are independently selected from the group consisting of:
hydrogen; C1-10 alkyl; aryl C0-8 alkyl; pyridine; and C3-10 cycloalkyl which is unsubstituted or substituted with COOH or NR5CNHNH2;
and R8, R9, R10, and R11 are independently selected from the group consisting of
H; NR5SO2C6-10 Aryl; NHHeterocycle; and C6-10 Aryl;
or a pharmaceutically acceptable salt, solvate, or metabolic precursor thereof.
Particular compounds according to the present invention include the following compounds which name has been provided by the AUTONOM(trademark) software:
Compound I: 2-benzylsulfonylamino-3-{[7-(5-aminopentyloxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-propionic acid TFA salt.
Compound II: 2-benzylsulfonylamino-3-{[7-(5-guanidinopentyloxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-propionic acid hydrochloride.
Compound III: 2-benzylsulfonylamino-3-{[7-(3-aminopentyloxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-propionic acid TFA salt.
Compound IV: 2-benzylsulfonylamino-3-{[7-(5-guanidinopropyloxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-propionic acid hydrochloride.
Compound V: xe2x80x2(trans)-2-{[7xe2x80x2-(3xe2x80x3-amino-propoxy)-4xe2x80x2-oxo-4xe2x80x2H-quinolizine-3xe2x80x2-carbonyl]-amino}-cyclohexanecarboxylic acid trifluoroacetic acid salt.
Compound VI: xe2x80x27(r,s)-3-benzoyloxycarbonylaminopropyl)oxo-3-carboxy-3-phenylsulfonylamino-1-yl)aminocarbonylaminoethyl)quinolizin-4-one.
Compound VII: xe2x80x27(r,s)-3-((aminopropyl)oxo-3-carboxy-3-phenylsulphonylamino-1-yl)aminocarbonylaminoethyl)quinolizin-4-one.
Compound VIII: xe2x80x27(r,s)-((3-guanidinoaminopropyl)oxy-3-carboxy-1pyridyl1-ethyl)aminocarbonylamino)quinolizin-4-one.
Compound IX: 2-Benzenesulfonylamino-3-{3-[7-(3-guanidino-propoxy)-4-oxo-4H-quinolizin-3-yl]-ureido}-propionic acid trifluoroacetate.
Compound X: 3-Phenyl-3-{[7-(3-benzyl-ureidopropoxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-propionic acid.
Compound XI: 3-{[7-(3-tert-Butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionic acid ethyl ester.
Compound XII: (S)-2-Benzenesulfonylamino-3-({7-[3-(3-methyl-ureido)-propoxy]-4-oxo-4H-quinolizine-2-carbonyl}-amino)-propionic acid.
Compound XIII: 7-(3-amino-propyloxy)-4-oxo-4H-quinolizine-2-carboxylic acid TFA salt.
Compound XIV: 2-Benzenesulfonylamino-3-{[7-(3-amino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionic acid TFA salt.
Compound XV: 2-Benzenesulfonylamino-3-{[7-(3-guanidino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionic acid hydrochloride.
Compound XVI: 3-{[7-(3-amino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionic acid TFA salt.
Compound XVII: 2-Benzenesulfonylamino-3-{[7-(4-amino-butoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionic acid TFA salt.
Compound XVIII: 2-Benzenesulfonylamino-3-{[7-(4-guanidino-butoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionic acid hydrochloride.
Compound XIX: 2-Benzenesulfonylamino-3-{[7-(4-amino-ethoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionic acid.
Compound XX: 2-Benzenesulfonylamino-3-{[7-(4-guanidino-ethoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionic acid.
Compound XXI: 3-{[7-(3-Amino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2xe2x80x94(pyrimidin-2-ylamino)-propionic acid hydrochloride.
Compound XXII: 3-{[7-(3-Guanidino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2xe2x80x94(pyrimidin-2-ylamino)-propionic acid hydrochloride.
Compound XXIII: 3-{[7-(3-Amino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-(benzenesulfonyl-methyl-amino)-propionic acid trifluoroacetace.
Compound XXIV: 2-(Benzenesulfonyl-methyl-amino)-3-{[7-(3-guanidino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionic acid hydrochloride.
Compound XXV: xe2x80x22-benzenesulfonylamino-3-({4-oxo-7-[3-(pyrimidin-2-ylamino)-propoxy]-4H-quinolizine-2-carbonyl}-amino)-propionic acid
Compound XXVI: 3-[(7-Aminomethyl-4-oxo-4H-quinolizine-2-carbonyl)-amino]-2-benzenesulfonylamino-propionic acid
Compound XXVII: 2-Benzenesulfonylamino-3-[(7-guanidinomethyl-4-oxo-4H-quinolizine-2-carbonyl)-amino]-propionic acid
Compound XXVIII: 3-[(7-Aminomethyl-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-2-carbonyl)-amino]-2-benzenesulfonylamino-propionic acid
Compound XXXIX: 2-Benzenesulfonylamino-3-[(7-guanidinomethyl-4-oxo-6,7,8,9-tetrahydro-4H-quinolizine-2-carbonyl)-amino]-propionic acid
Compound XXX: 3-{[8-(3-Amino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-benzenesulfonylamino-propionic acid trifluoroacetate.
Compound XXXI: 2-Benzenesulfonylamino-3-{[8-(3-guanidino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionic acid hydrochloride.
Compound XXXII: 3-{[8-(4-Amino-butoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-benzenesulfonylamino-propionic acid trifluoroacetate.
Compound XXXIII: 2-Benzenesulfonylamino-3-{[8-(4-guanidino-butoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionic acid hydrochloride.
Compound XXXIV: 3-{[8-(5-Amino-pentyloxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-benzenesulfonylamino-propionic acid trifluoroacetate.
Compound XXXV: 2-Benzenesulfonylamino-3-{[8-(5-guanidino-pentyloxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionic acid hydrochloride.
Compound XXXVI: 3-{[8-(2-amino-ethylamino)-4-oxo-4H-quinolizine-3-carbonyl)-amino}-3-phenyl-propionic acid
Compound XXXVII: 3-{[8-(2-Carbamimidoylsulfanyl-ethylamino)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionic acid trifluoroacetate.
Compound XXXVIII: 3-({4-Oxo-8-[2-(pyridin-3-ylthiocarbamoylsulfanyl)-ethylamino]-4H-quinolizine-3-carbonyl}-amino)-3-phenyl-propionic acid trifluoroacetate.
Compound XXXIX: 3-[(8-{Methyl-[2-(N-methyl-guanidino)-ethyl]-amino}-4-oxo-4H-quinolizine-3-carbonyl)-amino]-3-phenyl-propionic acid trifluoroacetate.
Compound XL: 3-{[8-(4xe2x80x94Carbamimidoyl-piperazin-1-yl)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionic acid trifluoroacetate.
Compound XLI: 3-{[8-(4-Guanidino-cyclohexylamino)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionic acid trifluoroacetate.
Compound XLII: (+/xe2x88x92)-3-(3,5-Dichlorophenyl)-3-((7-guanidinomethyl-4-oxo-4H-quinolizine-2-carbonyl)-amino]-propionic acid trifluoroacetic acid salt.
Compound XLIII: (+/xe2x88x92)-3-[(7-guanidinomethyl-4-oxo-4H-quinolizine-2-carbonyl]-amino)-3-pyridin-3-yl-propionic acid bis-trifluoroacetic acid salt.
Compound XLIV: (+/xe2x88x92)-3-[(7-guanidinomethyl-4-oxo-4H-quinolizine-2-carbonyl)-amino]-2-(pyrimidin-2-ylamino)-propionic acid bis-trifluoroacetic acid salt.
Compound XLV: (S)-2-Benzenesulfonylamino-3-([(7-benzyloxycarbonylamino-methyl)-4-oxo-4H-quinolizine-2-carbonyl]-amino)-propionic acid.
Compound XLVI: (S)-2-Benzenesulfonylamino-3-([4-oxo-7-(pyrimidin-2-ylaminomethyl)-4H-quinolizine-2-carbonyl]-amino)-propionic acid trifluoroacetic acid salt.
Compound XLVII (S)-2-Benzenesulfonylamino-3-{[7-(3-benzyl-ureidomethyl)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionic acid.
Compound XLVIII: (S)-2-Benzyloxycarbonylamino-3-[(7-guanidinomethyl-4-oxo-4H-quinolizine-2-carbonyl)-amino]-propionic acid trifluoroacetic acid salt.
Compound XLIX: (S)-3-[(7-guanidinomethyl-4-oxo-4H-quinolizine-2-carbonyl)-amino]-2-(2,4,6-trimethyl-benzenesulfonylamino)-propionic acid hydrochloride.
The term xe2x80x9cquinolizinonexe2x80x9d refers to 
The definition of quinolizinone also includes a tetrahydraquinolizinone wherein the ring involving atoms 5-10 may also be saturated.
The term xe2x80x9calkylxe2x80x9d as used herein represents a straight or branched, saturated or unsaturated chain having a specified total number of carbon atoms (i.e. C2 alkyl has two carbon atoms in the chain).
The term xe2x80x9cheterocylclexe2x80x9d as used herein represents an aromatic or non-aromatic hydrocarbon ring structure that contains in the ring structure one or more heteroatoms (O, S, or N). As used herein the term xe2x80x9clinkedxe2x80x9d heterocycle refers to a heterocycle wherein the ring members are linked to another chemical structure by a defined structure such as an amine or an alkyl.
The term xe2x80x9cbetweenxe2x80x9d in defining a range is meant to include the number that define the range (eg. between 3 and 7 means all numbers including 3 and 7).
It should be understood that reference to the structures representing xe2x80x94Jxe2x80x94Kxe2x80x94L and Kxe2x80x94Yxe2x80x94Z have a left side and a right side. The left side of a substituent group defining J and X is bound to the quinolizinone scaffoled. The left side of a group defining K and Y bind to J and X respectively. The left side of a substituent group defining L and Z bind to K and Y respectively.
The term xe2x80x9cphenylxe2x80x9d or xe2x80x9cbenzenexe2x80x9d represents a six member aromatic carbon containing ring whether or not the ring is a substituent group or otherwise.
The term xe2x80x9caminoxe2x80x9d includes primary amines i.e. NH2, secondary amines i.e. NHR, or tertiary amines i.e. N(R)2 wherein R is C1-4 alkyl. Also encompassed by the term are quaternary amines such as xe2x80x94NH3+.
The term xe2x80x9cguanadinoxe2x80x9d refers to the following structure: 
The term xe2x80x9cguanadino containing moietyxe2x80x9d refers to a moiety that has one carbon bound to three nitrogen.
The term xe2x80x9cureaxe2x80x9d refers generally to the following structure: 
The term xe2x80x9curea containing moietyxe2x80x9d refers to a moiety that contains a carbon bound to two nitrogen atoms and an oxygen atom.
The term xe2x80x9carylxe2x80x9d as defined herein refers to an aromatic ring having specified number of carbons (i.e. C2 has two carbons) that may optionally be substituted with one or more heteroatoms selected from the group consisting of O, N, and S.
The term xe2x80x9cpyrimidinylxe2x80x9d represents a six member aryl that contains two nitrogen atoms separated by carbon.
The term xe2x80x9csulfonylxe2x80x9d refers to a compound with the following structure: 
The above terms also includes salts, esters, and salts of esters of the above corresponding structures unless designated otherwise.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d shall mean non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts include the following salts: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabramine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamaote, palmitate, panthothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, trifluoroacetate, and valerate.
Compounds illustrated herein may be illustrated with incomplete valence. Such compounds, are intended to represent compounds with complete valence at all atoms. In such an instance where a compound has incomplete valence, it is intended that that atom has additional xe2x80x94H atoms bound to it to complete the valence.
Compounds of the present invention are chiral; included within the scope of the present invention are racemic mixtures and separated enantiomers of the general formula. Furthermore, all diastereoisomers of the general formula are included in he present scope. Furthermore, hydrates as well as anhydrous compositions and polymorphs of the general formula are within the present invention.
Prodrugs, such as ester derivatives of described compounds, are compound derivatives which, when absorbed into the bloodstream of a warm-blooded animal, cleave in such a manner as to release the drug form and permit the drug to afford improved therapeutic efficacy.
The term xe2x80x9cpharmaceutically effective amountxe2x80x9d shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system or animal that is being sought by a researcher or clinician.
In the schemes and examples below, various reagent symbols have the following meanings:
BOC: t-butyloxycarbonyl
Pd-C: palladium on activated carbon catalyst
DMF: dimethylformamide
DMSO: dimethylsulfoxide
CBZ: carbobenzyloxy
CH2Cl2: methylene chloride
CHCl3: chloroform
EtOH: ethanol
MeOH: methanol
EtOAc: ethylacetate
HOAc: acetic acid
BOP: Benzotriazol-1-yloxytris (dimethylamino) phosphonium, hexafluorophosphate
EDC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
Oxone: potassium peroxymonosulfate
TDA: lithium diisopropylamide
PYCLU: chloro-N,N,Nxe2x80x2,N,-bis (pentamethylene) formamidium hexafluorophosphate;
The present invention also includes methods of making compounds of formula I or II or any of the other formulas disclosed herein. Compounds of the present invention can be synthesized using conventional preparative steps and recovery methods known to those skilled in the art of organic chemistry. Synthetic routes according to one or more embodiments of the invention are illustrated in the following Schemes A-G and described below.
Preparation of a 7,3-Quinolizinone Framework
As per Scheme A, a compound A-1 such as 5-hydroxy-2-methylpyridine is treated with strong base such as n-butyl lithium in an anhydrous solvent, for example THF, at low temperature and then coupled with diethyl ethoxymethylene malonate. The resulting alkylated product is converted into 7-hydroxy-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester by refluxing in an aromatic solvent such as xylenes. The compound A-2 such as 7,3-quinolizinone ester is then treated with a strong base such as NaH, in an anhydrous solvent, and the resulting anion is reacted with compatibly functionalised -Lxe2x80x94Kxe2x80x94Jxe2x80x94Lg bearing if necessary appropriate protecting groups and wherein Lxe2x80x2g is a leaving group. Hydrolysis of the ethyl ester is done by treating the compound A-3 such as.the coupled quinolizinone with an hydroxide such as lithium hydroxide. The resulting acid compound A-4 is coupled with appropriately functionalised nucleophiles bearing the xe2x80x94Lxe2x80x94Kxe2x80x94J in its masked or current form in a solvent such as DMF in the presence of a coupling reagent such as (O-(7-azobenzotriazol-1-yl)-1,3,3-tetramethyluronium hexafluorophosphate), HATU, to provide compound A-5 such as functionalised 7,3-quinolozinone. Someone versed in the art of organic synthesis will recognize that the preparation of A-5 as described in this invention may require the use of protecting groups compatible with the synthetic sequence and removed when required. Alternatively and if more appropriate, the functionality xe2x80x94Xxe2x80x94Yxe2x80x94Z could be introduced first onto protected quinolizinones A6 as described for A-4 to give compound A-7, which after deprotection to A-8 can then be coupled as described for A-4 to give A-5. It shall be further understood that functional group interconversions can be carried out at any stage of the synthesis provided that reaction conditions for such conversions are compatible with other structural moieties. When compatibility problems are encountered, protecting groups could be used prior to functional group interconversion. 
Preparation of 7,2 and 8,2 Quinolizinone Framework
Core 7-hydroxy and 8-hydroxy-4-oxo-4H-quinolizine-2-carboxylic acid methyl esters are prepared using Scheme B.
Hence, for the 7,2-substituted framework compound B-1 such as, 2-methyl-5-hydroxy-pyridine is treated with a strong base such as NaH in anhydrous DMSO and then alkylated using, for example, benzyl bromide. The resultant benzyloxy pyridine such as compound B-2 is then oxydised with an agent such as 3-chioroperoxybenzoic acid (MCPBA) in a solvent such as dichioromethane to give the pyridine-N-oxide (compound B-3), which after stirring in hot acetic anhydride (100xc2x0 C.) provides 2-acetoxymethyl-5-benzyloxy pyridine. This compound B-3 is then stirred in a solvent such as methanol and treated with base such as potassium carbonate. The resulting alcohol is oxidised with an oxidizing agent such as MnO2 in dry solvent for example dichloromethane in order to obtain compound B-4. Wittig coupling reaction between, for example 2-(diethoxyphosphonyl)-succinic acid dimethyl ester, (Rxe2x80x2=C1-C8 straight chain alkyl) and 5-benzyloxy-pyridine-2-carbaldehyde in a solvent such as THF and using base like NaH provides the vinolygous adduct (compound B-5). This compound B-5 can be cyclised in heated solvents, for instance xylenes, in the presence of acid typically p-toluenesulfonic acid in order to obtain compound B-6. Debenzylation of the resulting quinolizinone in a solvent mixture such as dioxane/methanol In the presence of palladium over charcoal under hydrogen atmosphere provides compound B-7 such as the core 7-hydroxy-4-oxo-4H-quinolizine-2-carboxylic acid methyl ester.
The 8-hydroxy regioisomer is obtained from the same synthetic approach with the use of 2-methyl-6-hydroxypyridine.
Rxe2x80x2=C1-8 straight chain alkyl. 
Preparation of 7.2 and 8.2 Substituted Quinolizinone Integrin Inhibitors
7,2 and 8,2 functionalised quinolizinones can be prepared as per synthetic scheme C. Essentially, C-3 is prepared from B-7 by using the same synthetic approach as described for A-5 from A-2 in scheme A.
It shall be further understood that functional group interconversions can be carried out at any stage of the synthesis provided that reaction conditions for such conversions are compatible with other structural moieties. When compatibility problems are encountered, protecting groups could be used prior to functional group interconversion. 
Preparation of 7 or 8 Aminomethyl Linked Quinolizinones
When C-7 or C-8 carbon linked quinolizinones are desired, these are prepared as per Scheme D. The compound D-1, corresponding to B-7, such as 7-hydroxy-4-oxo-4H-quinolizine-2-carboxylic acid methyl ester is reacted with an anhydride such as triflic anhydride and the resulting leaving group is displaced by cyanide ion by using for example potassium cyanide in the presence of paladium. Resulting compound D-2 such as 7-cyanoquinolizinone is treated with hydrogen in the presence of paladium over charcoal, followed by protection of the amino or coupling with Lxe2x80x94Kxe2x80x94Jxe2x80x94Lxe2x80x2g to give D-2. Compound D-3 such as 7-tert-butoxycarbonylamino-methyl-4-oxo-4H-quinolizine-2-carboxylic acid methyl ester is reacted with base, such as lithium hydroxide and then coupled with a nucleophillc group comprising Xxe2x80x94Yxe2x80x94Z to provide compound D-4. Compound D-4 results from coupling with Lxe2x80x94Kxe2x80x94Jxe2x80x94Lxe2x80x2g, using coupling reagents such as HATU and reactions well known in the art, and aminomethyl intermediates obtained after the removal of protecting group Pg from the C-7 amino substitutent.
Treatment of D-6 with a base such as lithium hydroxide, followed with coupling reaction to a nucleophilic group comprising xe2x80x94Xxe2x80x94Yxe2x80x94Z in the presence of a coupling reagent such as HATU provides 7-carbon linked quinolizinones of formula D-5 as described herein.
An alternative route to 7-cyano quinolizinone D-2 is depicted in scheme D. Thus, treatment of 5-Cyano-2-methylpyridine D-01 with an oxydising agent such as selenium dioxide in a solvent such as dioxane provided pyridine aldehyde D-02 which can be coupled with diethyl ethoxymethylene malonate under anhydrous basic conditions, obtained for example with NaH in tetrohydrofuran. The resulting adduct is converted directly to D-02 by refluxing in an aromatic solvent such as xylenes.
It shall be further understood that functional group interconversions can be carried out at any stage of the synthesis provided that reaction conditions for such conversions are compatible with other structural moieties. When compatibility problems are encountered, protection groups could be used prior to functional group interconversion.
When C-8 aminomethyl quinolizinones are desired, it will be appreciated that the same synthetic route as depicted in Scheme D could be used when 4-cyano-2-methylpyridine is used instead of 5-cyano-2-methylpyridine compound D-01. 
Preparation of 7 or 8 Aminomethyl Linked Tetrahydroquinolizinones
C-7 or C-8 carbon linked tetrahydroquinolizinones are prepared according to scheme E in which the synthetic route is illustrated for the C-7 tetrahydroquinolizinone E-3. Hence, E-3 is prepared from E-1 or E-4 using the general scheme process described for converting D-6 or D-4 into D-5 from scheme D. E-1 is prepared by treating 7-Cyanoquinolizinones D-2 first with excess H2/Pd/C followed with coupling of 7-aminomethyltetrahydroquinolizinone with a nucleophile comprising Lxe2x80x94Kxe2x80x94Jxe2x80x94Lxe2x80x2g. E-4 is obtained by treating D-2 first with excess H2/Pd/C, then protecting the 7-aminomethyl group as per the art, followed with basic hydrolysis with a base such as lithium hydroxide and coupling with a nucleophile comprising xe2x80x94Xxe2x80x94Yxe2x80x94Z.
It shall be understood that functional group Interconverslons can be carried out at any stage of the synthesis provided that reaction conditions for such conversions are compatible with other structural moeities. When compatibility problems are encountered, protecting groups could be used prior to functional group interconversion. 
Preparation of 8,3 and 8,2-Substituted Quinolizinone Series Bearing an Amino Linker in the Lxe2x80x94Kxe2x80x94J Group.
As in Scheme F, the compound F-1 is 4-chloro-2-methylpyridine and is treated with a strong non nucleophilic base such as lithium diisopropylamide and then coupled with diethyl ethoxymethylene malonate. The resulting adduct F-2 is cyclized in refluxing solvent such as xylenes to provide after basic hydrolysis (eg. LiOH) compound F-3 such as 8-chloro-4-oxo-4H-quinolizine-3-carboxylic acid. This compound F-3 is then coupled with nucleophiles incorporating the group xe2x80x94Xxe2x80x94Yxe2x80x94Z in the presence of a coupling reagent such as HATU, typically in a dry solvent such as DMF. The resulting adduct (compound F-4) can then be coupled with aminomethylbenzene and treated with base, for example lithium hydroxide, to afford after debenzylation compound F-5, which can then be used to prepare 8,3-disusbtituted quinolizinone F-6 by coupling F-5 with Lxe2x80x94Kxe2x80x94Jxe2x80x94Lxe2x80x2g wherein Lxe2x80x2g is a leaving group.
Other analogs are prepared by treating the compound F-4 with nucleophilic groups comprising Lxe2x80x94Kxe2x80x94J in the presence or absence of base in dry solvent to provide compound F-7. It shall be further understood that functional group interconversions can be carried out at any stage of the synthesis provided that reaction conditions for such conversions are compatible with other structural moieties. When compatibility problems are encountered, protecting groups could be used prior to functional group interconversion.
8,2-substituted quinolizinones containing an amino linker are prepared by following Scheme F, as described above, provided that 5-chloro-2-methyl pyridine is used instead of F-1. 
Solid Phase Approach To Synthesize 8, 3. Series Quinolizinones
Such as described in Scheme G, substituted amino propionic acid, G-1, is suitably protected with an amino protecting group such as Fmoc. The protected compound, G-2, is anchored to a resin such as Wang resin to.produce G-3. After deprotection of the amino group of G-3, it is then coupled to a quinolizinone carboxylic acid derivative via standard peptide coupling techniques to give compound G-4. Substitution of the chlorine group of G-4 employing monoamines or diamines furnished G-5 and G-6, respectively. Compound G-6 can be further elaborated through reactions of the free terminal amine. 
It will be appreciated by those skilled in the art that the compounds or formulas I and II depending on the substituents, may contain one or more chiral centers and thus exist in the form of many different isomers, optical isomers (i.e. enantiomers) and mixtures thereof including racemic mixtures. All such isomers, enantiomers and mixtures thereof including racemic mixtures are included within the scope of the invention.
One embodiment of the present invention comprises a method or inhibiting an integrin using a compound of formula I and II or any compound or formula disclosed herein that falls within the definition of formula I and II.
Another embodiment of the present invention comprises a method for inhibiting an xcex1v integrin using a compound of formula I, II, or any compound or formula disclosed herein that falls within the definition of formula I and II.
Another embodiment of the present invention comprises a method for inhibiting xcex1vxcex23 using a compound of formula I, II, or any compound or formula disclosed herein that falls within the definition of formula I and II.
In yet another embodiment of the present invention comprises a method for inhibiting xcex1vxe2x8ax965 using a compound of formula I or II or any compound or formula disclosed herein that falls within the definition of formula I or II.
Another embodiment of the present invention comprises a method for inhibiting angiogenesis using a compound of formula I or II or any compound or formula disclosed herein that falls within the definition of formula I or II.
Another embodiment of the present invention comprises a method for preventing a cell from binding to osteopontin using a compound of formula I or II or any compound or formula disclosed herein that falls within the definition of formula I or II.
Another embodiment of the present invention comprises a method for preventing a cell from binding to fibronectin using a compound of formula I or II or any compound or formula disclosed herein that falls within the definition of formula I or II.
Another embodiment of the present invention comprises a method for treating a tumor using a compound of formula I or II or any compound or formula disclosed herein that falls within the definition of formula I or II. In another aspect of this invention, the tumor is a solid tumor. Such solid tumors include but are not limited to tumors for cancers that originate in the lung, breast, liver, kidney, brain, pancreas, ovary, uterus, testes, gastrointestinal tract, skin and prostate. The present is for treatment of mammals such as humans.
Another embodiment of the present invention comprises a method for treating cancer using a compound of formula I or II or any compound or formula disclosed herein that falls within the definition of formula I or II.
Another embodiment of the present invention comprises a method for treating foot in mouth disease using a compound of formula I or II or any compound or formula disclosed herein that falls within the definition of formula I or II.
One embodiment of the present invention also provides compositions which comprise a pharmaceutically acceptable carrier or adjuvant and an effective amount of a compound of formula I or II to inhibit angiogenesis and/or tumor growth in a mammal. The proportion of each carrier, diluent or adjuvant is determined by the solubility and chemical nature of the compound and the route of administration according to standard pharmaceutical practice.
Therapeutic and prophylactic methods of this embodiment of the invention comprise the step of treating patients in a pharmaceutically acceptable manner with those compounds or compositions. Such compositions may be in the form of tablets, capsules, caplets, powders, transdermal patches, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
In order to obtain consistency of administration, it is preferred that a composition of the invention is in the form or a unit dose. The unit dose presentation forms for oral administration may be tablets and capsules and may contain conventional excipients. For example, binding agents, such as acacia, gelatin, sorbitol, or polyvinylpyrrolidone; fillers, such as lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tableting lubricants such as magnesium stearate; disintegrants, such as starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.
The compounds may be injected parenterally; this being intramuscularly, intravenously, or subcutaneously. For parenteral administration, the compound may be used in the form of sterile solutions containing other solutes, for example, sufficient saline or glucose to make the solution isotonic. The amount of active ingredient administered parenterally will be approximately 0.01 to 250 mg/kg/day, preferably about 1 to 10 mg/kg/day, more preferably about 0.5 to 30 mg/kg/day, and more most preferably about 1-20 mg/kg/day.
The compounds may be administered orally in the form of tablets, capsules, or granules containing suitable excipients such as starch, lactose, white sugar and the like. The compounds may be administered orally in the form of solutions which may contain coloring and/or flavoring agents. The compounds may also be administered sublingually in the form of tracheas or lozenges in which each active ingredient is mixed with sugar or corn syrups, flavoring agents and dyes, and then dehydrated sufficiently to make the mixture suitable for pressing into solid form. The amount of active ingredient administered orally will depend on bioavailability of the specific compound. The amount of active ingredient administered orally will be approximately 0.01 to 250 mg/kg/day, preferably about 1 to 10 mg/kg/day, more preferably about 0.5 to 30 mg/kg/day, and more most preferably about 1-20 mg/kg/day.
The solid oral compositions may be prepared by conventional methods of blending, filling, tableting, or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art. The tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
Oral liquid preparations may be in the form of emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may or may not contain conventional additives. For example suspending agents, such as sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, or hydrogenated edible fats; emulsifying agents, such as sorbitan monooleate or acaci; non-aqueous vehicles (which may include edible oils), such as almond oil, fractionated coconut oil, oily esters selected from the group consisting of glycerine, propylene glycol, ethylene glycol, and ethyl alcohol; preservatives, for instance methyl para-hydroxybenzoate, ethyl parahydroxybenzoate, n-propyl parahydroxybenzoate, or n-butyl parahydroxybenzoate of sorbic acid; and, if desired, conventional flavoring or coloring agents.
For parenteral administration, fluid unit dosage forms may be prepared by utilizing the peptide and a sterile vehicle, and, depending on the concentration employed, may be either suspended or dissolved in the vehicle. Once in solution, the compound may be injected and filter sterilized before filling a suitable vial or ampoule and subsequently sealing the carrier or storage package. Adjuvants, such as a local anesthetic, a preservative or a buffering agent, may be dissolved in the vehicle prior to use. Stability of the pharmaceutical composition may be enhanced by freezing the composition after filling the vial and removing the water under vacuum, (e.g., freeze drying the composition). Parenteral suspensions may be prepared in substantially the same manner, except that the peptide should be suspended in the vehicle rather than being dissolved, and, further, sterilization is not achievable by filtration. The compound may be sterilized, however, by exposing it to ethylene oxide before suspending it in the sterile vehicle. A surfactant or wetting solution may be advantageously included in the composition to facilitate uniform distribution of the compound.
The pharmaceutical composition of this invention comprise a compound of formula I or II and a pharmaceutically acceptable carrier, diluent or adjuvant. Typically, they contain from about 0.1% to about 99% by weight of active compound, and preferably from about 10% to about 60% by weight depending on which method of administration is employed.
A pharmaceutically effective amount of compounds of the invention can be determined according to one or more of the assays described in detail in the examples. Under these particular conditions, a compound having such activity will exhibit an IC50 of approximately 50 xcexcg/ml or less, preferably 25 xcexcg/ml or less, more preferably 10 xcexcg/ml or less, and most preferably less than 1 xcexcg/ml.
Physicians will determine the dosage of the present therapeutic agents which will be most suitable. Dosages may vary with the mode of administration and the particular compound chosen. In addition, the dosage may vary with the particular patient under treatment. The dosage of the compound used in the treatment will vary, depending on viral load, the weight of the patient, the relative efficacy of the compound and the judgment of the treating physician. Such therapy may extend for several weeks or months, in an intermittent or uninterrupted manner.